B3.051 Prework Aplastic Anemia

Question 1

how is severe aplastic anemia classified?

Answer 1

bone marrow cellularity <30%
depression of at least 2 of the following 3 hematopoietic lineages:
-neutrophil < 0.5
-retic <60 w transfusion dependence
-platelet <20

Question 2

how is moderate aplastic anemia classified

Answer 2

decreased bone marrow cellularity

depression of 2/3 lineages not fulfilling the prior criteria

Question 3

what is fanconi anemia

Answer 3

most common cause of inherited bone marrow failure syndrome (IBMFS)
autosomal recessive
chromosomes particularly susceptible to DNA cross linking agents

Question 4

what genetic defect leads to fanconi?

Answer 4

at least 16 defined
most common is a mutation in FANCA on chrom 16
most mutations mess up cellular response to DNA damage, especially interstrand cross linking

Question 5

what agents are used to test for fanconi?

Answer 5

ICL agents

DEB or MMC

Question 6

what is dyskeratosis congenita

Answer 6

another cause of IBMFS
mutations in genes of the telomere repair complex leading to premature death of rapidly proliferating cells
X-linked more common

Question 7

genetic defects associated with DC

Answer 7

X linked: DKC1 gene

autosomal dom: TERC and TERT

Question 8

2 other causes of IBMFS

Answer 8

shwachman-diamond syndrome

severe congenital neutropenia

Question 9

pathogenesis of shwachman-diamond syndrome

Answer 9

exocrine pancreatic insufficiency with secondary steatorrhea, blood cell deficiencies, and skeletal abnormalities
mutations in the SBDS genes on 7q11 which induced accelerated cellular apoptosis via the FAS pathways

Question 10

pathogenesis of severe congenital neutropenia

Answer 10

heterozygous mutations in the ELA2/ELANE gene

Question 11

why rule out inherited causes?

Answer 11

treatment different, immune suppression doesn’t work
at risk of other medical problems including cancer
family needs genetic counseling

Question 12

causes of primary acquired aplastic anemia

Answer 12

idiopathic aplastic anemia
pregnancy-associated aplastic anemia
AA/PNH syndrome

Question 13

causes of secondary acquired

Answer 13

drug associated
iatrogenic/cytotoxic
idiosyncratic
radiation associated 
viruses (EBV, CMV)
hepatitis/ aplastic anemia syndrome
pancytopenia of autoimmune disease

Question 14

what is PNH

Answer 14

paroxysmal nocturnal hemoglobinuria
rare bone marrow failure disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias
the absence of 2 GPI anchored proteins, CD 55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations
due to somatic mutations

Question 15

what are 2 ways that pathogens can affect hematopoietic stem cells

Answer 15

direct toxic effects

indirect effects through immunologic mediation

Question 16

supportive measures for aplastic anemia

Answer 16

symptoms can be corrected with transfusions
infections addressed with broad spectrum antibiotics in presence of fever and severe neutropenia
overuse of blood products should be avoided, as they may cause allo-immunizations

Question 17

what is the preferred first therapy in young people with AA

Answer 17

matched sibling HSCT

bone marrow is preferred source of stem cells, not peripheral blood

Question 18

discuss the primary immunosuppressive therapy agent used for AA

Answer 18

principal agent is ATG (anti-thymocyte globulin) which is manufactured by delivering human T cells to a horse/rabbit
immunized animals produce Abs to the Ags on the T cell
removed and purified and administered to human to deplete lymphocytes

Question 19

what is ATG used in combo with

Answer 19

cyclosporine
calcineurin inhibitor that inhibits IL-2 production
prednisone used as prophylaxis for serum sickness

Question 20

discuss eltrombopag

Answer 20

TPO receptor agonist
improves blood counts
response rate of 40%

Question 21

time to response to h-ATG/CsA therapy

Answer 21

10-12 weeks

response rate 60-80%

Question 22

cause of AGVHD

Answer 22

mature donor T cells present in the allograft acting against host “antigens”
initiating trigger is believed to be epithelial cell injury
most prone tissues are skin, GI mucosa, and bile ducts

Question 23

cause of CGVHD

Answer 23

beyond 100 days
mainly mediated by new T and B cells that are derived from HSCs or other early progenitors in the graft
more indolent course

Question 24

presentation of AGVHD

Answer 24

rash, diarrhea, elevated liver function tests

severe cases can lead to sepsis

Question 25

what tumor is most affected by graft versus tumor effect?

Answer 25

CML